: This proposal is a continuation of the drug discovery efforts in the area of nucleosides at the University of Georgia and Emory University/VA Medical Center. This renewal application is concerned with the chemistry and biology of newly emerged L-nucleosides andis in search of novel anti-HIV agents which do not confer cross-resistance with existing nucleoside anti-HIV modalities. Recently, several L-nucleosides including 3TC, FTC, L-FddC, L-FMAU have been discovered as promising anti-HIV/anti-HBV agents. The proposed L- nucleosides will be studied in combination or as single agents against drug-resistant viral strains. Additionally, nucleoside phosphate dimers will be investigated in search of anti-HIV agents which inhibit a viral specific enzyme, integrase. The following four classes of nucleosides are proposed for synthesis and for biological and biochemical evaluation: (1) D- and L-2',3'-dideoxy- and 2',3'-didehydro-2',3'-dideoxy- nucleosides; (2) D- and L-carbocyclic nucleosides; (3) L-C-nucleosides; (4) nucleoside phosphate dimers. The long-term goal of this application is to develop novel clinically useful anti-HIV nucleosides which do not confer cross resistance with the existing anti-HIV modalities.